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Their pathomechanisms are complex and not fully understood. Recent studies have revealed that complement system proteins and interactors are dysregulated in disc degeneration and Modic changes. The complement system is part of the innate immune system and plays a critical role in tissue homeostasis. However, its dysregulation has also been associated with various pathological conditions such as rheumatoid arthritis and osteoarthritis. Here, we review the evidence for the involvement of the complement system in intervertebral disc degeneration and Modic changes. We found that only a handful of studies reported on complement factors in Modic changes and disc degeneration. Therefore, the level of evidence for the involvement of the complement system is currently low. Nevertheless, the complement system is tightly intertwined with processes known to occur during disc degeneration and Modic changes, such as increased cell death, autoantibody production, bacterial defense processes, neutrophil activation, and osteoclast formation, indicating a contribution of the complement system to these spinal pathologies. Based on these mechanisms, we propose a model how the complement system could contribute to the vicious cycle of tissue damage and chronic inflammation in disc degeneration and Modic changes. With this review, we aim to highlight a currently understudied but potentially important inflammatory pathomechanism of disc degeneration and Modic changes that may be a novel therapeutic target.<\/jats:p>","DOI":"10.1002\/jsp2.1312","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T06:35:36Z","timestamp":1706855736000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["The role of the complement system in disc degeneration and\n                    <scp>Modic<\/scp>\n                    changes"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3064-8364","authenticated-orcid":false,"given":"Irina","family":"Heggli","sequence":"first","affiliation":[{"name":"Center of Experimental Rheumatology, Department of Rheumatology University Hospital Zurich, University of Zurich  Zurich Switzerland"},{"name":"Department of Physical Medicine and Rheumatology Balgrist University Hospital, Balgrist Campus, University of Zurich  Zurich Switzerland"},{"name":"Leni and Peter W. 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